PROJECT SUMMARY/ABSTRACT Boys and men are diagnosed with autism spectrum disorder (ASD) about four times more frequently than girls and women. This skewed diagnostic ratio has historically made it difficult to recruit sufficient numbers of girls with ASD to conduct well-powered analyses of sex differences. Thus, the preponderance of the evidence upon which we base inferences about ASD etiology, developmental trajectories, and phenotypes comes from studies in which girls and women with ASD were either excluded entirely, or included at a ratio of 4:1 or less. However, recent research specifically focused on girls and women with ASD suggests that male versus female ASD may have fundamentally different characteristics. Better understanding the biological mechanisms of female-specific developmental trajectories of ASD risk and resilience is crucial to improving ascertainment and optimizing treatment, because the etiological systems involved may provide insight into sex-specific phenotypic expression and targets for intervention. A new data collection in the National Database for Autism Research (NDAR), Multimodal Developmental Neurogenetics of Females with Autism (collection #2021) may help investigators better characterize female ASD by providing imaging, omics, and phenotyping data for a large, sex-balanced cohort of children with and without ASD. In preliminary work with this dataset, we found that ASD girls showed a profile distinct from both typically developing girls and ASD boys, which was characterized by motor (M1) and striatal (STR) hypoactivation to social stimuli, and greater size of rare copy number variants (CNVs) affecting genes expressed in these brain regions. The Female Protective Effect (FPE), on the other hand, involved greater recruitment of the executive control brain network (including dorsolateral prefrontal cortex [dlPFC]). These findings suggest that the striatomotor-cortical system may be implicated in female-specific processes of ASD risk and protection, but do not fully delineate the biological mechanisms by which such effects operate. We propose secondary analysis of de-identified data from this NDAR collection in order to further specify these mechanisms. We aim, first, to examine sex- and diagnosis-specific differences in functional connectivity between striatal and motor/frontal regions, and degree of coexpression of M1-, STR-, and frontal-expressed genes. We hypothesize that, for girls with ASD versus typically developing girls, we will find reduced functional connectivity between STR and targets in motor and frontal cortex. Second, we will assess coexpression of genes impacting striatomotor-cortical system development. We expect to observe a greater degree of coexpression of genes that are both 1) expressed in these brain regions, and 2) affected by CNVs in girls with ASD (versus boys with ASD), reflecting a disruption to the striatomotor-cortical system underlying brain functional differences in girls with ASD. Finally, we will explore how functional connectivity and genetic load in the striatomotor-cortical system are associated with phenotypic characteristics including social behavior, restricted/repetitive patterns of behavior and interests, and executive function.